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Editorials
repeat the exact test that Ray Owen had used to develop the Grandmother Effect hypothesis (even though Ray specifically invited others to do so2). A torrent of publica- tions followed his, which were not able to confirm his observations of 1954. Meanwhile, other societal changes were occurring, particularly the advent of formula-fed babies, no longer exposed for long periods to breast milk.
Schonewille et al. therefore used a novel approach to the problem, based on the breast-feeding history of the mother provided by the grandmother. The hypothesis was that breast-feeding would condition a baby girl such that anti- body response to any non-inherited erythrocyte antigens, including RhD, but also others for which prophylaxis was not done, would be inhibited. When encountered in later life, as she becomes pregnant, they hypothesized that these breast milk exposures from the grandmother would dimin- ish her chances of developing specific antibodies to her hus- band’s (inherited paternal) antigens (IPAs) expressed by her child’s rbc.
To test whether there is indeed a cross-generational effect of the grandmother, preventing the daughter from produc- ing antibodies to her baby’s rbc and causing hemolytic dis- ease of the newborn, Schonewille et al. chose to study preg-
Figure 1. The Grandmother Effect. Grandmother [x -/+] gives birth to a baby girl, who grows into a women [x -/-] whose immune system bears the memory of exposure to a red blood cell (rbc) antigen (X) that she did NOT inherit but remains in her body at low levels due to microchimerism (Mc; the situation where foreign cells--in this case the grandmother's-- although rare, persist in blood and tissues). Mother(x -/-) then conceives a child by a father whose rbc expresses the very same non-inherited maternal antigen (NIMA;=x). If the newly-conceived child inherits this gene from the father (x encodes an inherited paternal antigen, or IPA), then the mother, during preg- nancy, recalls her exposure to this "grandmother" antigen and is less likely to form an anti-x antibody response, thus protecting the fetus.
nancies in cases where mothers had already developed the potential for hemolytic disease. In these women, in the period 1987-2008, their as yet unborn children were being treated by intrauterine transfusion, and their pregnancies managed with the most up-to-date techniques. The inves- tigators studied the antibody responses of the mothers to inherited paternal antigens (IPA) expressed by their babies in relation to various factors, including the breast-feeding history of the maternal grandmother. This approach took the focus off of in utero exposure only and put it onto the combination of in utero exposure and breast-feeding. Schonewille and colleagues made two critically important and novel observations: 1) that there was indeed a Grandmother Effect limiting the mother’s ability to produce anti IPA antibodies to a variety of erythrocyte antigens; and 2) that the capacity for a Grandmother Effect was time- dependent: i.e., it developed only after at least two months of breast-feeding of the mother by the grandmother. The power of the study was considerable, since the study was done on 125 3-generational Dutch families (grandmothers, mothers, and babies) exposed to 330 non-D rbc antigens and involved the measurement of antibody responses to each of these. Both highly as well as weakly immunogenic
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